Single Lung Tumor Contains 50,000 Mutated Genes

WEDNESDAY May 26, 2010 -- Malignant lung tumors may contain not one, not two, but potentially tens of thousands of genetic mutations which, together, contribute to the development of the cancer.

A sample from a lung tumor from a heavy smoker revealed 50,000 mutations, according to a report in the May 27 issue of Nature.

"People in the field have always known that we're going to end up having to deal with multiple mutations," said Dr. Hossein Borghaei, director of the Lung and Head and Neck Cancer Risk Assessment Program at Fox Chase Cancer Center in Philadelphia. "This tells us that we're not just dealing with one cell line that's gone crazy. We're dealing with multiple mutations. Every possible pathway that could possibly go wrong is probably found among all these mutations and changes."

The revelation does pose "additional difficulties" for researchers looking for targets for better treatments or even a cure for lung and other types of cancer, said study senior author Zemin Zhang, a senior scientist with Genentech Inc. in South San Francisco.

Frustrating though the findings may seem, the knowledge gleaned from this and other studies "gives investigators a starting point to go back and look and see if there is a common pathway, a common protein that a couple of different drugs could attack and perhaps slow the progression," Borghaei said.

The researchers examined cells from lung cancer samples (non-small-cell lung cancer) belonging to a 51-year-old man who had smoked 25 cigarettes a day for 15 years.

"If you look at the number of cigarettes this person has consumed over his lifetime versus the number of mutations accumulated, for every three cigarettes you have you get a new mutation," Zhang noted.

The researchers were initially surprised to hit upon so many genetic mutations -- some new and some previously known -- surprised enough to conduct additional analyses to validate the findings.

They found that many of the mutations were redundant, meaning that many of them affected components of the same pathway.

"The key to survival for cancer cells is redundancy: hit multiple pathways, mutate as much as you possibly can and then you can survive anything that comes at you," Borghaei explained.

The authors point out that this is one analysis from one patient. Other patients with lung cancer will have different mutational profiles, as will other tumor types.

And this particular tumor was smoking-related, with all of the damage conferred by cigarette carcinogens.

"In this particular case, it's smoking-related," Zhang said. "When you have a patient who has a long history of smoking, you can tell that most of the mutations are mediated by carcinogens, so we anticipate that we will observe a lot more mutations in such a [patient]."

The same is likely to be true of melanoma, because much of the damage here is caused by UV radiation, Zhang added, but the number of mutations in breast and prostate cancer, for instance, is likely to be much lower.